Neuromedin-N inhibits migrating myoelectric complex and induces irregular spiking in the small intestine of rats; comparison with neurotensin.

The effects of neuromedin-N on migrating myoelectric complexes in the small intestine of rats were studied. As neuromedin-N and neurotensin are structurally related peptides a comparison with neurotensin was made. Myoelectric activity was recorded by means of three bipolar electrodes implanted into the wall of the small intestine at 5, 15 and 25 cm distal to the pylorus. The peptides were administered as intravenous infusions to fasted conscious rats. Neuromedin-N at doses of 100-800 pmol kg-1 min-1 caused a dose-dependent disruption of the migrating myoelectric complexes and induced irregular spiking activity (n = 7, P less than 0.05). Neurotensin induced a similar response, but at doses of 1.0-8.0 pmol kg-1 min-1 (n = 5, P less than 0.05). Thus, on a molar basis, neuromedin-N appeared to be about 100-times less potent than neurotensin. Hexamethonium (20 mg kg-1 i.v.) inhibited the migrating motor complexes and induced quiescence, but did not block the effect of neuromedin-N at a dose of 800 pmol kg-1 min-1. Atropine (1 mg kg-1 i.v.) and mepyramine (2 mg kg-1 i.v.) did not affect the migrating motor complexes, nor did they block the effect of neuromedin-N. Simultaneous infusion of neuromedin-N and neurotensin in a 1:1 molar ratio at doses of 2 pmol kg-1 min-1 showed inhibition of the response to neurotensin in eight out of ten experiments. In conclusion, neuromedin-N changes the myoelectric activity in the small intestine from a fasting to a fed pattern.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that bombesin releases extragastric gastrin in man

Bombesin-induced gastrin release from extragastric sources has been investigated in two groups of patients without gastric antrum: 11 patients with total gastrectomy and 11 patients with subtotal (Billroth II) gastrectomy. A 30-min bombesin infusion (5 ng . kg-1 . min-1) caused a prompt significant gastrin increase (P less than 0.05) in both groups of patients. The gastrin response to bombesin was significantly (P less than 0.005) lower in patients without antral tissue than in the control group (n = 7). The individual peak gastrin responses, in totally (TG) and subtotally (SG) gastrectomized patients, were significantly over basal levels (TG: peak 100.3 +/- 12 vs. basal 62.8 +/- 9.1, P less than 0.005; SG: peak 96.9 +/- 9.4 vs. basal 72.4 +/- 6.8, P less than 0.001; pg/ml, mean +/- S.E.M.). These data indicate that bombesin acts not only on antral G cells, but on all gastrin cells in the gastrointestinal tract.     

GLP-1 and GLP-2 act in concert to inhibit fasted,but not fed,small bowel motility in the rat

Small bowel motility was studied in rats at increasing (1-20 pmol/kg/min) intravenous doses of either glucagon-like peptide-1 (GLP-1) or glucagon-like peptide-2 (GLP-2) alone, or in combination in the fasted and fed state. There was a dose-dependent inhibitory action of GLP-1 on the migrating myoelectric complex (MMC), where the dose of 5 pmol/kg/min induced an increased MMC cycle length. No effect was seen with GLP-2 alone, but the combination of GLP-1 and GLP-2 induced a more pronounced inhibitory effect, with significant increase of the MMC cycle length from a dose of 2 pmol/kg/min. During fed motility, infusion of GLP-1 resulted in an inhibition of spiking activity compared to control. In contrast, infusion of GLP-2 only numerically increased spiking activity compared to control, while the combination of GLP-1 and GLP-2 resulted in no change compared to control. In summary, this study demonstrates an additive effect of peripheral administration of GLP-1 and GLP-2 on fasted small bowel motility. In the fed state, GLP-1 and GLP-2 seem to display counter-balancing effects on motility of the small intestine.     

Progressive weakening of the response of key enzymes of liver glycogen metabolism to permanently increased plasma epinephrine levels

In adult male rats anaesthetized with pentobarbital the intravenous infusion of 0.5 micrograms.kg-1.min-1 of epinephrine increased liver phosphorylase a activity within 5 min, whereas later a weakening of the hormone effect was observed. After increasing the infusion rate to 1.0 micrograms.kg-1.min-1 and extending the study to more parameters, the diminishing effect on phosphorylase was confirmed and a similar response was established for liver cAMP. Concomitantly, a decrease and recovery of liver glycogen synthase a activity was observed. In rats with permanent catheters in one of their tail arteries for obtaining blood samples, the plasma epinephrine levels were shown to be permanently increased (from cca 1 pmol.ml-1 before infusion of 1.0 micrograms.kg-1.min-1 to more than 30 pmol.ml-1 during infusion) and remained at steady levels throughout the infusion. Therefore, the weakening of the epinephrine effect should be ascribed to changes at (or beyond) the catecholamine receptor level. A hitherto undescribed decrease of total glycogen synthase activity was observed during the infusions.     

Atrial natriuretic factor release during acute infusion of isoproterenol in the conscious rat.

The effect of beta-adrenergic stimulation on atrial natriuretic factor (ANF) release was studied in conscious rats. 20-min infusion of 85 or 850 ng kg-1 min-1 isoproterenol (ISO) resulted in positive inotropic and chronotropic responses and no elevation of atrial pressures. A slight increase in plasma ANF, together with a drop in blood pressure, were observed only in the group infused with the higher dose. During the infusion of 850 ng kg-1 min-1 ISO, there was no relationship between plasma ANF and any of the haemodynamic parameters, with the exception of mean arterial pressure (r = 0.72, P less than 0.05, n = 9). Larger doses (greater than 3 micrograms kg-1 min-1) were toxic. We conclude that beta-adrenergic stimulation is not an important stimulus for ANF release when diastolic resting tension is low.     

Effect of vasoactive intestinal polypeptide on porcine gastrointestinal electrical activity

The influence of intravenous infusion of VIP, 150 and 300 pmol/kg/min, on gastrointestinal electrical activity was studied in conscious piglets with electrodes implanted in the wall of the antrum pylori, duodenum, jejunum, and ileum. Both doses resulted in a decrease in antral electrical activity. In the small intestine, only the lower dose caused a shortening of the irregular spiking activity phase in the jejunum and ileum. In the jejunum this resulted in a reduction of the MMC interval. It may be concluded that the prevailing effect of VIP is an inhibition of gastrointestinal electrical activity in the piglet.     

Insulin does not mediate the attenuation of fatigue associated with glucose infusion in rat plantaris muscle.

Glucose infusion attenuates fatigue in rat plantaris muscle stimulated in situ, and this is associated with a better maintenance of electrical properties of the fiber membrane (Karelis AD, Péronnet F, and Gardiner PF. Exp Physiol 87: 585-592, 2002). The purpose of the present study was to test the hypothesis that elevated plasma insulin concentration due to glucose infusion ( approximately 900 pmol/l), rather than high plasma glucose concentration ( approximately 10-11 mmol/l), could be responsible for this phenomenon, because insulin has been shown to stimulate the Na+-K+ pump. The plantaris muscle was indirectly stimulated (50 Hz, for 200 ms, 5 V, every 2.7 s) via the sciatic nerve to perform concentric contractions for 60 min, while insulin (8 mU x kg-1x min-1: plasma insulin approximately 900 pmol/l) and glucose were infused to maintain plasma glucose concentration between 4 and 6 [6.2 +/- 0.4 mg x kg-1x min-1: hyperinsulinemic-euglycemic (HE)] or 10 and 12 mmol/l [21.7 +/- 1.1 mg. kg-1. min-1: hyperinsulinemic-hyperglycemic clamps (HH)] (6 rats/group). The reduction in submaximal dynamic force was significantly (P < 0.05) less with HH (-53%) than with HE and saline only (-66 and -70%, respectively). M-wave characteristics were also better maintained in the HH than in HE and control groups. These results demonstrate that the increase in insulin concentration is not responsible for the increase in muscle performance observed after the elevation of circulating glucose.     

Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of regulatory peptides on the porcine lower oesophageal sphincter

Studies were performed to investigate the effects of neurotransmitters and neurotransmitter candidates (substance P, VIP, somatostatin, Met-enkephalin, gastrin-17, CCK-4 and -8, neurotensin and TRH) of the newly discovered peptidergic nervous system on lower oesophageal sphincter pressure in anaesthetized pigs. All neuropeptides were infused over 2 min periods in 6 different doses, separated by resting periods of at least 1 min, directly into the arterial supply of the lower oesophageal sphincter. Substance P caused a dose-dependent increase in lower oesophageal shpincter pressure; the threshold dose was 9 pmol . kg-1 . min-1 and half maximal response occurred at 72 pmol . kg-1 . min-1. None of the other polypeptides, however, influenced the resting lower oesophageal sphincter. These studies show that substance P is a potent stimulant of smooth muscle in the lower oesophageal sphincter, suggesting that this peptide may be an important regulator of lower oesophageal sphincter pressure.     

The effect of atropine on bombesin and gastrin releasing peptide stimulated gastrin, pancreatic polypeptide and neurotensin release in man

The effects of 1-h infusions of bombesin and gastrin releasing peptide (GRP) at 50 pmol/kg per h and neurotensin at 100 pmol/kg per h on gastrin, pancreatic polypeptide (PP) and neurotensin release in man were determined following either saline or atropine infusion (20 micrograms/kg). Bombesin produced a rise in plasma neurotensin from 32 +/- 6 to 61 +/- 19 pmol/l and of PP from 26 +/- 8 to 36 +/- 7 pmol/l. There was a further rise of plasma PP to 50 +/- 13 pmol/l after cessation of the infusion. GRP had no significant effect on plasma neurotensin, but compared to bombesin, produced a significantly greater rise in plasma PP from 34 +/- 6 to 66 +/- 19 pmol/l during infusion. There was no post-infusional increase. At this dose, GRP was as effective as bombesin in releasing gastrin, although unlike bombesin its effect was enhanced by atropine. Neurotensin produced a rise in plasma PP from 17 +/- 4 to 38 +/- 8 pmol/l. Atropine blocked the release of PP during GRP and neurotensin infusion. Atropine had no effect on neurotensin or PP release during bombesin infusion, but did block the rise in plasma PP following bombesin infusion. We conclude that, in contrast to meal-stimulated neurotensin release, bombesin-stimulated neurotensin release is cholinergic independent. Despite structural homology, bombesin and GRP at the dose used are dissimilar in man in their actions and sensitivity to cholinergic blockade.     

Effect of somatostatin infusion on VIP-induced transport changes in the human jejunum

This study was designed to elucidate the mechanism by which somatostatin administration ameliorates or abolishes diarrhea in pancreatic cholera syndrome (PCS). Absorption (or secretion) of water and electrolytes was measured in 30-cm segments of jejunum of 18 healthy volunteers in whom PCS was mimicked by intravenous infusion of VIP. Using the triple-lumen tube technique, the intestine was perfused with a plasma-like electrolyte solution while administering intravenous saline (control), VIP (400 pmol/kg/hr), somatostatin (5000 pmol/kg/hr), or VIP plus somatostatin. VIP infusion abolished water and electrolyte absorption and somatostatin had no effect on these VIP-induced transport changes regardless of whether somatostatin infusion was started before or after VIP infusion. Somatostatin infusion had no effect on VIP plasma concentration when elevated by intravenous VIP infusion (control: 10 +/- 1 pmol/l; during VIP infusion: 108 +/- 6). In a patient with pancreatic cholera syndrome identical perfusion experiments showed jejunal water secretion (93 ml/30 cm/hr) which changed to absorption (65 ml/30 cm/hr) when somatostatin was infused (5000 pmol/kg/hr). Plasma VIP concentration fell from 145 to 74 pmol/l (normal less than 50) during somatostatin infusion. Stool weight fell from 3722 g to 819 g per 24 hours when somatostatin was given at a dose of 2500 pmol/kg/hr for two days. Our observations in healthy subjects show that somatostatin has no effect on intestinal transport at the mucosal level when circulating VIP concentration is elevated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of somatostatin on organ blood flow in anaesthetized cats

Effect of somatostatin infusion (100 ng/min-61 pmol/min) on organ blood flow was studied in anaesthetized cats. Total blood flow in the superior mesenteric, left renal, lienal, inferior caval veins and the sagittal sinus was measured by the H2-clearance method. Vascular resistance decreased in the small intestine, in the hind limb and in the kidney due to somatostatin infusion. Somatostatin seems to have direct vasodilatory effect in different vascular beds.     

Surface pH responses of muscles of different fiber-type composition to catecholamines

Catecholamines were infused intravenously for 45 min into pentobarbital sodium-anesthetized rabbits. Physiologically low-dose epinephrine (0.125 microgram . min-1 . kg-1) decreased medial gastrocnemius (MG) surface pH (SpH) 0.16 +/- 0.03 (SD) (P less than 0.001) to a low of 7.25 +/- 0.11 and soleus (S) SpH 0.09 +/- 0.04 (P less than 0.01) to a low of 7.33 +/- 0.08 without changing blood pressure significantly. Surface temperature measurements suggested a statistically insignificant small increase in local blood flow in both muscles. With 1.25 microgram . min-1 . kg-1 epinephrine, MG SpH decreased 0.22 +/- 0.05 (P less than 0.001) to a low of 7.17 +/- 0.06 and S SpH decreased 0.10 +/- 0.05 (P less than 0.02) to a low of 7.26 +/- 0.04. The MG SpH decrease exceeded the S SpH decrease in each experiment for both epinephrine infusion levels, and the incremental difference was significantly greater (P less than 0.02) with the higher dose, demonstrating a dose-response effect more pronounced for glycolytic compared with oxidative fibers. Norepinephrine infusions of 1.25 and 2.5 micrograms . min-1 . kg-1 did not change SpH of either muscle significantly, despite increases in blood pressure of 10 +/- 3 (P less than 0.002) and 19 +/- 10 mmHg (P less than 0.02), respectively.     

The activity front of the migrating motor complex of the human stomach but not of the small intestine is motilin-dependent

The role of motilin in the generation of the gastric component of phase 3 of the migrating myoelectric complex (MMC) was studied in human volunteers. Interdigestive motor activity was recorded manometrically in five normal subjects after a fast of at least 15 h. Intraluminal pressures were measured in the gastric antrum at 4 levels 3 cm apart and in the upper small bowel at 3 levels 25 cm apart. Blood samples were drawn every 10 min for radioimmunoassay of motilin and PP. After 2 spontaneously occurring activity fronts (AF) had been recorded, bovine PP was infused intravenously at a rate of 50 μg/h. Following the third AF a combination of PP (50 μg/h) and 13-norleucine-motilin (30 μg/h) was infused until after the next AF. It was found that 90% of the spontaneous AFs originated in the stomach. They were preceded by a motilin peak. During the PP infusion, plasma PP levels increased from 29 to 256 pmol/l, motilin decreased from 42 to 15 pmol/l, and all AFs originated in the small bowel. During the combined PP and motilin infusion, plasma motilin increased to 330 pmol/l, and all AFs again originated in the stomach. It is concluded that motilin has an important role in the regulation of the MMC activity front in the stomach, but not in the small intestine. Postprandial rises in plasma PP might be involved in lowering motilin levels after a meal, and indirectly, in the disruption of gastric MMCs during digestion.     

Ventilatory effects of substance P, vasoactive intestinal peptide, and nitroprusside in humans.

Animal studies suggest that the neuropeptides, substance P and vasoactive intestinal peptide (VIP), may influence carotid body chemoreceptor activity and that substance P may take part in the carotid body response to hypoxia. The effects of these peptides on resting ventilation and on ventilatory responses to hypoxia and to hypercapnia have been investigated in six normal humans. Infusions of substance P (1 pmol.kg-1.min-1) and of VIP (6 pmol.kg-1.min-1) were compared with placebo and with nitroprusside (5 micrograms.kg-1.min-1) as a control for the hypotensive action of the peptides. Both peptides caused significantly less hypotension than nitroprusside. Substance P and nitroprusside caused significantly greater increases in ventilation and in the hypoxic ventilatory response than VIP. No changes were seen in hypercapnic sensitivity. The stimulation of ventilation and the differential effects on ventilatory chemosensitivity that accompanied hypotension are consistent either with stimulation of carotid body chemoreceptor activity or with an interaction with peripheral chemoreceptor input to the respiratory center, as is seen in animals. The similar cardiovascular but different ventilatory effects of the peptides suggest that substance P may also stimulate the carotid body in a manner independent of the effect of hypotension. This is consistent with a role of substance P in the hypoxic ventilatory response in humans.     

Effect of vagotomy and atropine on plasma somatostatin response to a meal in conscious dogs

In 4 conscious dogs with gastric fistulas the somatostatin responses to a meal were measured and compared to the responses seen after i.v. infusion of atropine sulfate (20 and 50 micrograms.kg-1.h-1) or cimetidine (8 mg.kg-1.h-1). The experiments were repeated after truncal vagotomy. The somatostatin responses to bombesin (0.5 micrograms.kg-1.h-1) were also measured before and after vagotomy. Vagotomy decreased basal and postprandial somatostatin levels and reduced the somatostatin responses to feeding during the first 30-min period following the ingestion of the meal but not during subsequent periods. Bombesin-induced somatostatin release was increased after vagotomy. Atropine decreased the somatostatin responses to the meal before and after vagotomy. Cimetidine had no significant effect. These studies suggest that, in conscious dogs, somatostatin released into the circulation is partly under vagal control and that, as for gastrin release, vagal pathways for stimulation and inhibition are present. Our studies also suggest that cholinergic mechanisms are involved in the control of postprandial somatostatin release.     

Exercise, dobutamine, and combined atropine, norepinephrine, and epinephrine compared

We compared the cardiovascular effects evoked in conscious dogs by 1) submaximal exercise; 2) infusion of dobutamine (40 micrograms X kg-1 X min-1); and 3) infusion of a combination of atropine (0.15 mg/kg), norepinephrine (0.19 micrograms X kg-1 X min-1), and epinephrine (0.05 micrograms X kg-1 X min-1). Myocardial O2 demand, as estimated by the double product (heart rate X systolic blood pressure), was similar during all three interventions. Cardiac output and heart rate increased significantly (P less than 0.05) during each of the three interventions. Arteriovenous O2 difference and total body O2 consumption, however, increased only during submaximal exercise. Although myocardial blood flow increased similarly during each of the three interventions, blood flow to skeletal muscle and the tongue increased only during exercise. Exercise and the combined infusion of atropine, norepinephrine, and epinephrine produced similar increases in blood flow to the diaphragm and similar decreases in blood flow to the stomach. These changes in blood flow were associated with appropriate changes in vascular resistance. Additionally, blood flow to the brain, kidney, adrenal glands, liver, and intestine did not change during any of the three interventions. Thus, in dogs, submaximal exercise, infusion of dobutamine, and infusion of a combination of atropine, norepinephrine, and epinephrine to evoke a given level of estimated myocardial O2 consumption produce similar increases in cardiac output, heart rate, and myocardial blood flow. In contrast, the changes in total body O2 consumption, arteriovenous O2 difference, regional blood flow, and regional vascular resistance that occur during each of these three interventions are different.     

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

Excess cortisol has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P < 0.05), hypercortisolemia resulted in higher glucose (P < 0.05) and free fatty acid concentrations (P < 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P < 0.01), indicating the presence of steroid-induced insulin resistance. Postabsorptive glucose production (P = 0.64) and the fractional contribution of gluconeogenesis to EGR (P = 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P < 0.05), implying a decrease in net glucose effectiveness (4.42 +/- 0.52 vs. 6.65 +/- 0.83 ml.kg-1.min-1; P < 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 +/- 0.24 vs. 3.82 +/- 0.51 ml.kg-1.min-1; P < 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P < 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-3H]glucose during hydrocortisone than during saline infusion (P < 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal beta-cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess impairs glucose tolerance by decreasing both insulin action and glucose effectiveness.     

Gastro-intestinal tract function in sheep infused with somatostatin

The effect of a 5-day continuous intravenous infusion of somatostatin (4.6 ng min-1 kg-1) was studied, using anoestrous ewes given 791 g dry matter per day of a 60:40 lucerne hay:oat grain pelleted diet from a continuously moving belt. 51Cr-EDTA, 103Ru-phenanthroline and lignin were used as markers to determine digesta mean retention times (MRT) by a continuous infusion-total sampling procedure. The somatostatin infusion increased the concentration of somatostatin in venous plasma within the physiological range from 10 to 76 ng/l, decreased plasma concentrations of prolactin and thyroxine, but had no effect upon plasma concentrations of insulin and glucagon. It had no effect upon digesta-free weight of the rumen and omasum but consistently decreased the weight of all post-ruminal segments of the gastrointestinal (GI) tract. The infusion increased the accumulation of digesta in the abomasum and caecum. Total MRT of all three markers in the entire GI tract was unaffected by somatostatin infusion, but the proportion of total MRT spent in the abomasum + small intestine + caecum increased and the proportion spent in the large intestine and rumen decreased. Somatostatin infusion decreased apparent endogenous abomasal secretion, increased water flow from the rumen and into the abomasum and decreased voluntary water consumption. It is proposed that the prime site of somatostatin action was in the abomasal to caecal region, where somatostatin-secreting D cells are found in greatest concentration, that effects observed in the large intestine and rumen may represent secondary compensatory mechanisms and that the effects observed were due to direct action of somatostatin and were not mediated by other GI hormones.     

Effect of substance P on cardiovascular and respiratory function in subjects

The effect of substance P (SP), administered both intravenously and by inhalation, has been studied in normal and asthmatic humans. Intravenous infusion of SP (0.2-3.3 pmol X kg-1 X min-1) achieving a plasma concentration of SP between 5 and 25 pM produced vasodilatation (mean +/- SD), maximal increase in skin temperature (0.9 +/- 0.3 degree C) (P less than 0.05), and fall in diastolic blood pressure (8.5 +/- 2.9 mmHg) (P less than 0.05) associated with an increase in heart rate (15 +/- 10 beats/min) (P less than 0.05). All subjects had a fall in Vp30 (airflow at 70% of forced vital capacity measured from total lung capacity after a forced partial expiratory flow maneuver) at low infusion rate (P less than 0.05) and a significant rise at the highest infusion rate (P less than 0.05). Ventilation at rest and when stimulated by transient hypoxia increased (mean increase in resting ventilation 0.73 +/- 0.4 l/min and mean percent increase in transient ventilatory hypoxic response 41 +/- 27%). There was a small nonsignificant increase in plasma norepinephrine but no change in epinephrine or histamine. Inhaled SP, up to 0.7 mumol, caused a small nonsignificant fall in airway function in asthmatic subjects. SP has demonstrable effects on vascular smooth muscle and control of ventilation but at the doses studied had little effect on airway function.